Longitudinal Clinical and Cognitive Changes Along the Alzheimer Disease Continuum in Down Syndrome

Abstract

Key Points Question Are age, intellectual disability (ID), and clinical status associated with Alzheimer disease (AD) progression and longitudinal cognitive decline in adults with Down syndrome (DS)? Findings In this cohort study of 632 adults with DS, there was a high age-dependent risk of developing symptomatic AD but not the prodromal stage of the disease. ID stratification was not associated with longitudinal cognitive decline, and the study found both practice and floor effects. Meaning These findings show the need for health plans to screen for AD in adults with DS and provide important data to inform AD clinical trials.

The Global Deterioration Scale for Down Syndrome Population (GDS-DS): A Rating Scale to Assess the Progression of Alzheimer’s Disease

“…The criterion to be placed in this stage was that the subject did not endure the neuropsychological examination proposed in the protocol and this was, in turn, an exclusion criterion for the PD group on which the present work is based. Some DS adults in the symptomatic stages of AD are not able to complete a neuropsychological examination [ 22 ]. The authors of the present study agree, as routine follow-up visits have encountered this setback.…”

“…Declines in the CAMCOG-DS total score have been shown to be related to changes in all of the stages of the GDS-DS. A decline in performance on CAMCOG-DS has been found in the entire AD-DS continuum [ 13 , 26 , 28 , 62 ], regardless of whether the level of ID is mild or moderate [ 22 ]. Interestingly, performance on CAMCOG-DS is linked to amyloid deposition [ 71 ], and it is recommended that longitudinal studies assess cognitive changes related to ID and dementia [ 72 ].…”

“…For stage 6 (advanced Alzheimer’s disease), an additional criterion was established. Based on our clinical experience and other studies of populations with DS, it has been suggested that some tests cannot be administered to those with advanced stages of AD or in populations with severe intellectual disabilities [ 57 ] because they do not provide enough information due to the “floor effect” [ 22 ]. Therefore, the criterion of not being able to administer all or any cognitive tests from the screening protocol to participants would, on its own, be an indicator of advanced AD, supported by affected adaptive skills.…”

“…Additionally, mild behavioral impairment (MBI) [ 19 , 20 ] has been proposed as a prodromal neuropsychiatric stage of emergent dementia. Due to the high risk of developing AD in subjects with DS, and considering that AD-DS pharmacological interventions are not efficient enough [ 21 , 22 ], it is necessary to arrange a grading scale that captures the whole clinical spectrum of the AD-DS with the inclusion of these recently proposed diagnostic categories to detect early therapeutic windows.…”

Basal forebrain cholinergic neurons are vulnerable in a mouse model of Down syndrome and their molecular fingerprint is rescued by maternal choline supplementation

“…[3][4][5][6][7][8] Individuals with DS also display the onset of neurodegeneration associated with Alzheimer's disease (AD) in early midlife, including amyloid plaques, neurofibrillary tangles, and cognitive decline, with age-associated escalation. [9][10][11][12][13][14][15][16] While persons with DS have significantly improved lifespans due to medical intervention, [17][18][19][20] these individuals have increased health complications, with the development of dementia accounting for >70% of deaths in individuals over the age of 35. 21 Age-related cognitive decline in DS and AD is associated with degeneration of the cholinergic basal forebrain system, including neuronal loss in subregions of the basal forebrain and specific loss of cholinergic basal forebrain neurons in the nucleus basalis and cholinergic fiber projections to the hippocampus and neocortex.…”